1. Field of Invention
This invention relates to tumor inhibiting pharmaceutical compositions, methods of inhibiting the growth of mammalian tumors, the phenylquinolinecarboxylic acids and derivatives thereof useful in such compositions and methods.
2. Literature Background
Cinchophen, 2-phenyl-4-quinoline carboxylic acid, has been known for many years and has been described as being useful as an antirheumatic and in the treatment of gout. Cinchophen has the formula: ##STR1##
Many cinchophen and cinchoninic acid derivatives have been prepared in investigating the Pfitzinger reaction and for use in color photographic developing.
Buu-Hoi et al. [J. Chem. Soc., 386-8 (1953)] report 2-arylcinchoninic acids, prepared by the Pfitzinger reaction, having the formula: ##STR2## where R=H, CH.sub.3, C.sub.2 H.sub.5 and phenyl;
Ar=fluoro-substituted phenyl; and PA0 R"=H, Br, Cl or CH.sub.3. PA0 R.sup.2 is, inter alia, phenyl and halo-substituted phenyl; and PA0 R.sup.4 is CN, CO.sub.2 H and related esters and amides. PA0 R=H, CH.sub.3, C.sub.2 H.sub.5 and other groups; and PA0 Ar can be a variety of aromatic groups including 4-biphenylyl, 4-alkylphenyl and 4-phenoxyphenyl. PA0 R'=H, CH.sub.3 or CF.sub.3 ; and PA0 R"=H, F, Cl, CH.sub.3 or OCH.sub.3. PA0 R.sub.1 is, inter alia, H or lower alkyl; and PA0 R is, inter alia, aryl and heteroaryl, optionally substituted by alkyl, aryl and the like. PA0 R.sub.1 can be phenyl or phenyl substituted with Cl, CH.sub.3, OCH.sub.3 or NH.sub.2 ; and PA0 R.sub.2 can be CO.sub.2 H. PA0 R is CO.sub.2 H, CONH.sub.2 or CONH-alkyl; PA0 R.sub.1 may be H or lower alkyl; and PA0 R.sub.2 may be aryl or a heterocyclic group. PA0 R.sup.4 is CO.sub.2 H or CO.sub.2 R.sup.11 ; PA0 R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I, CH.sub.3, CF.sub.3, S(O).sub.n R.sup.12 or CH.sub.2 CH.sub.3, at least two of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 being H; PA0 R.sup.9 and R.sup.9A are independently H or alkyl of 1 to 3 carbon atoms; PA0 R.sup.10 is OH, OCH.sub.3, OCH.sub.2 CH.sub.3, NH.sub.2, NHCH.sub.3 or N(CH.sub.3).sub.2 ; PA0 R.sup.11 is (CH.sub.2).sub.2-4 NR.sup.9 R.sup.9A ; PA0 R.sup.12 is alkyl of 1-5 carbon atoms optionally substituted with one or more of F, Cl and Br; PA0 W, Y and Z are independently H, F, Cl, Br, alkyl of 1-5 carbon atoms, NO.sub.2, alkoxy of 1-5 carbon atoms, alkylthio of 1-5 carbon atoms, OH, CF.sub.3 or NH.sub.2 ; PA0 m is 0 or 1; PA0 n is 0 or 1; and PA0 q is 0, 1 or 2; or PA0 (1) R.sup.5, R.sup.6 and R.sup.7 cannot all be H; PA0 (2) when R.sup.4 is CO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2, R.sup.6 is CH.sub.2 CH.sub.3, or R.sup.7 is Cl, R.sup.1 cannot be cyclohexyl; PA0 (3) when R.sup.1 is cyclohexyl and R.sup.3 is H, R.sup.6 must be Cl or F, but R.sup.6 and R.sup.8 cannot both be Cl; and PA0 (4) when R.sup.6 is CH.sub.3, R.sup.7 cannot be Cl. PA0 R.sup.4 is CO.sub.2 H or CO.sub.2 R.sup.11 ; PA0 R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently H, F, Cl, Br, I, CH.sub.3, CF.sub.3, S(O).sub.n R.sup.12 or CH.sub.2 CH.sub.3, at least two of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 being H; PA0 R.sup.9 and R.sup.9A are independently H or alkyl of 1 to 3 carbon atoms; PA0 R.sup.10 is OH, OCH.sub.3, OCH.sub.2 CH.sub.3, NH.sub.2, NHCH.sub.3 or N(CH.sub.3).sub.2 ; PA0 R.sup.11 is (CH.sub.2).sub.2-4 NR.sup.9 R.sup.9A ; PA0 R.sup.12 is alkyl of 1-5 carbon atoms optionally substituted with one or more of F, Cl and Br; PA0 m is 0 or 1; PA0 n is 0 or 1; and PA0 q is 0, 1 or 2; or PA0 a pharmaceutically suitable salt thereof; PA0 (1) when R.sup.4 is CO.sub.2 H, R.sup.1 is phenyl or phenoxy, and R.sup.5, R.sup.7 and R.sup.8 are H, R.sup.6 cannot be Br; PA0 (2) R.sup.5, R.sup.6 and R.sup.7 cannot all be H; PA0 (3) when R.sup.4 is CO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2, R.sup.6 is CH.sub.2 CH.sub.3, or R.sup.7 is Cl, R.sup.1 cannot be cyclohexyl; PA0 (4) when R.sup.1 is cyclohexyl and R.sup.3 is H, R.sup.6 must be Cl or F, but R.sup.6 and R.sup.8 cannot both be Cl; PA0 (5) when R.sup.1 is 4-H.sub.2 NC.sub.6 H.sub.4 and R.sup.3 is H, R.sup.6 cannot be Cl and R.sup.8 cannot be Br; and PA0 (6) when R.sup.6 is CH.sub.3, R.sup.7 cannot be Cl. PA0 R.sup.3 is H or alkyl or 1-2 carbon atoms; PA0 R.sup.4 is CO.sub.2 H, a sodium or potassium salt thereof, or CO.sub.2 R.sup.11 ; PA0 R.sup.5 and R.sup.6 are independently H, halogen, CH.sub.3 or CF.sub.3 ; and PA0 R.sup.7 and R.sup.8 are independently H or halogen; PA0 or a pharmaceutically suitable salt thereof; PA0 (1) R.sup.5, R.sup.6 and R.sup.7 cannot all be H; PA0 (2) when R.sup.1 is cyclohexyl and R.sup.3 is H, R.sup.6 must be Cl or F, but R.sup.6 and R.sup.8 cannot both be Cl; and PA0 (3) when R.sup.6 is CH.sub.3, then R.sup.7 cannot be Cl. PA0 R.sup.3 is H or alkyl of 1-2 carbon atoms; PA0 R.sup.4 is CO.sub.2 H, a sodium or potassium salt thereof, or CO.sub.2 R.sup.11 ; PA0 R.sup.5 and R.sup.6 are independently H, halogen or CF.sub.3, provided that both R.sup.5 and R.sup.6 are not H; PA0 R.sup.11 is (CH.sub.2).sub.2-4 NR.sup.9 R.sup.9A ; and PA0 R.sup.9 and R.sup.9A are independently alkyl of 1 to 3 carbon atoms. PA0 R.sup.1 is phenyl, phenyl substituted with halogen, phenoxy, or phenoxy substituted with halogen; PA0 R.sup.3 is methyl; PA0 R.sup.5 is H or Cl; PA0 R.sup.6 is F or Cl; and PA0 R.sup.9 and R.sup.9A are methyl. PA0 (1) 2-(1,1'-Biphenyl-4-yl)-6-fluoro-3-methyl-4-quinolinecarboxylic acid, sodium or potassium salt. PA0 (2) 6-Fluoro-3-methyl-2-(4-phenoxyphenyl)-4-quinolinecarboxylic acid, sodium or potassium salt. PA0 (3) 2-(4'-Bromo-1,1'-biphenyl-4-yl)-6-fluoro-3-methyl-4-quinolinecarboxylic acid, sodium or potassium salt. PA0 (4) 2-(2'-Fluoro-1,1'-biophenyl-4-yl)-6-fluoro-3-methyl-4-quinolinecarboxylic acid, sodium or potassium salt. PA0 (5) 2-(1,1'-Biphenyl-4-yl)-5-chloro-6-fluoro-3-methyl-4-quinolinecarboxylic acid, sodium or potassium salt. PA0 (6) 6-Fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-[(2-dimethylamino)ethyl ]ester-4-quinolinecarboxylic acid, hydrochloride salt.
No use for these compounds is described.
Epling et al. [Tet. Lett., 23 (38), 3843-3846 (1982)] report ##STR3## as an intermediate to a new arylmethylsulfonyl chloride convertible to sulfonamides which can be photochemically cleaved.
Starke et al. in U.S. Pat. No. 4,009,020, issued Feb. 22, 1977, describe plant growth regulant cinchoninic acid derivatives, including those of the formula: ##STR4## where Z is H or halogen, preferably H;
Buu-Hoi et al. [J. Org. Chem., 18, 1209-1224 (1953)] describe 2-arylcinchoninic acids of the formula: ##STR5## where X=H or Br;
The compounds prepared were part of a program to investigate the toxicity of cinchoninic acids and quinolines, since cinchophen ("Atophan") can produce a degeneration of liver tissue of a possible precancerous nature. Some of the compounds prepared caused degenerative changes in the liver.
Buu-Hoi et al. [Rec. trav. Chim., 62 713-718 (1943)] report 2-(4-cyclohexylphenyl)cinchoninic acid and 2-(4-biphenylyl)cinchoninic acid. Hai et al. [J. Org. Chem., 23, 39-42 (1958)] describe 2-(4-cyclopentylphenyl)cinchoninic acids, including 3-methyl and 3-ethyl derivatives, and 6-bromo and 6-methyl derivatives. Buu-Hoi et al. [J. Org. Chem., 22, 668-671 (1957)] report 2-[4-(4-methoxy-3-chlorophenyl)phenyl]cinchoninic acid and its 3-methyl and 3-ethyl derivatives. Another Buu-Hoi report [idem., 24, 39-41 (1959)] describes the 2-methoxy-3-chlorophenyl isomer.
Yen et al. [J. Org. Chem., 23, 1858-1861 (1958)] report 2-phenyl- and 2-(4-fluorophenyl)-6-fluorocinchoninic acids for testing as potential carcinogens.
Steinkopf et al. [Annalen, 540, 7-14 (1939); idem, 543, 119-128 (1940)] report 2-(5-methyl- and 5-phenyl-2-thienyl)cinchoninic acids. Sy et al. [J. Chem. Soc., 1975-1978 (1954)] report 2-(5-t-butyl-2-thienyl)cinchoninic acid and its 3-methyl and 6-bromo derivatives.
Buu-Hoi et al. [Rec. trav. Chim., 72, 774-780 (1953)] report 2-[4-(4-hydroxy- and 4-methoxyphenyl)phenyl]cinchoninic acids and their 3-methyl derivatives.
Boykin et al. [J. Med. Chem., 11, 273-277 (1968)] report cinchoninic acids of the formula: ##STR6## where R=H, F, CH.sub.3 or OCH.sub.3 ;
Although prepared as part of an antimalarial program, it does not appear that these intermediates were tested for antimalarial activity.
Saggiomo et al. [J. Med. Chem., 11, 277-281 (1968)] report antimalarial quinoline-4-methanols derived from the corresponding acids. The latter include 6,8-dichloro-2-(3-trifluoromethylphenyl)cinchoninic acid and ethyl ester, and 2-(4-chlorophenyl)-6-fluorocinchoninic acid and ethyl ester.
Buu-Hoi et al. [Rec. trav. Chim., 70, 825-832 (1951)] report 2-(4-n-propyl-4'-biphenylyl)cinchoninic acid and 3-methyl-2-(4-ethyl-4'-biphenylyl)cinchoninic acid.
Coles, in U.S. Pat. No. 2,579,420, issued Dec. 18, 1951, describes the conversion of 6,8-dihalocinchoninic acids into 6-halo-8-hydroxycinchoninic acids useful as color formers. Disclosed are compounds of the formula: ##STR7## where X is Cl or Br;
Tulagin et al., in U.S. Pat. No. 2,524,741, issued Oct. 3, 1950, describe the use, in color photographic developing, of 8-hydroxyquinolines of the formula: ##STR8## where R is halogen, NO.sub.2 or SO.sub.3 H;
French Pat. No. 1,040,440 describes compounds similar to Tulagin et al., useful in color photographic chemistry, of the formula: ##STR9## where X is halogen;
German Pat. Nos. 659,496; 668,741; and 668,742 describe 2-phenylcinchoninic acids containing iodo groups and a free or etherified p-hydroxy substituent on the 2-phenyl group. Such compounds are stated to be useful as X-ray contrast agents.
Sakai et al., [Gann, 46, 605-616 (1955)] report that 2-phenyl-4-carboxyquinoline had no tumoricidal effect in in vitro test using NF mouse sarcoma.
U.S. Pat. No. 2,888,346 issued on May 26, 1959 to Tulagin and Hoffstadt describes compounds of the formula: ##STR10## where X.sup.1 is 6-Cl or X.sup.1 is 6-Cl and X.sup.2 is 8-Br, and their use to protect organic media from damage from ultraviolet radiation.